Controlled release metformin formulations

ABSTRACT

Sustained release pharmaceutical formulations comprising an antihyperglycemic drug or a pharmaceutically acceptable salt thereof are disclosed. The formulations provide therapeutic plasma levels of the antihyperglycemic drug to a human patient over a 24 hour period after administration.

[0001] The present application is a continuation of U.S. Ser. No.09/594,637 filed Jun. 15, 00 which is a continuation of U.S. Ser. No.09/045,330 filed Mar. 20, 1998, now issued as U.S. Pat. No. 6,099,859,the enclosures of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to controlled release unit doseformulations containing an antihyperglycemic drug. More specifically,the present invention relates to an oral dosage form comprising abiguanide such as metformin or buformin or a pharmaceutically acceptablesalt thereof such as metformin hydrochloride or the metformin saltsdescribed in U.S. Pat. Nos. 3,957,853 and 4,080,472 which areincorporated herein by reference.

[0003] In the prior art, many techniques have been used to providecontrolled and extended-release pharmaceutical dosage forms in order tomaintain therapeutic serum levels of medicaments and to minimize theeffects of missed doses of drugs caused by a lack of patient compliance.

[0004] In the prior art are extended release tablets which have anosmotically active drug core surrounded by a semipermeable membrane.These tablets function by allowing a fluid such as gastric or intestinalfluid to permeate the coating membrane and dissolve the activeingredient so it can be released through a passageway in the coatingmembrane or if the active ingredient is insoluble in the permeatingfluid, pushed through the passageway by an expanding agent such as ahydrogel. Some representative examples of these osmotic tablet systemscan be found in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,034,758,4,077,407 and 4,783,337. U.S. Pat. No. 3,952,741 teaches an osmoticdevice wherein the active agent is released from a core surrounded by asemipermeable membrane only after sufficient pressure has developedwithin the membrane to burst or rupture the membrane at a weak portionof the membrane.

[0005] The basic osmotic device described in the above cited patentshave been refined over time in an effort to provide greater control ofthe release of the active ingredient. For example U.S. Pat. Nos.4,777,049 and 4,851,229 describe an osmotic dosage form comprising asemipermeable wall surrounding a core. The core contains an activeingredient and a modulating agent wherein the modulating agent causesthe active ingredient to be released through a passageway in thesemipermeable membrane in a pulsed manner. Further refinements haveincluded modifications to the semipermeable membrane surrounding theactive core such as varying the proportions of the components that formthe membrane, i.e U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 orincreasing the number of coatings surrounding the active core, i.e U.S.Pat. No. 5,650,170 and 4,892,739.

[0006] Although vast amounts of research has been performed oncontrolled or sustained release compositions and in particular onosmotic dosage forms, very little research has been performed in thearea of controlled or sustained release compositions that employantihyperglycemic drugs.

[0007] The limited work on controlled or sustained release formulationsthat employ antihyperglycemic drugs such as metformin hydrochloride hasbeen limited to the combination of the antihyperglycemic drug and anexpanding or gelling agent to control the release of the drug from thedosage form. This limited research is exemplified by the teachings of WO96/08243 and by the GLUCOPHAGE® product which is a commerciallyavailable product from Bristol-Myers Squibb Co. containing metforminHCl.

[0008] It is reported in the 50th Edition of the Physicians' DeskReference, copyright 1996, p. 753, that food decreases the extent andslightly delays the absorption of metformin delivered by the GLUCOPHAGE®dosage form. This decrease is shown by approximately a 40% lower peakconcentration and a 25% lower AUC in plasma and a 35 minute prolongationof time to peak plasma concentration following administration of asingle GLUCOPHAGE® tablet containing 850 mg of metformin HCl with foodcompared to the similar tablet administered under fasting conditions.

[0009] It is an object of the present invention to provide a controlledor sustained release formulation for an antihyperglycemic drug whereinthe bioavailability of the drug is not decreased by the presence offood.

[0010] It is a further object of the present invention to provide acontrolled or sustained release formulation for an antihyperglycemicdrug that does not employ an expanding polymer.

[0011] It is also a further object of the present invention to provide acontrolled or sustained release formulation for an antihyperglycemicdrug that can provide continuous and non-pulsating therapeutic levels ofan antihyperglycemic drug to an animal or human in need of suchtreatment over a twelve hour to twenty-four hour period.

[0012] It is an additional object of the present invention to provide acontrolled or sustained release formulation for an antihyperglycemicdrug that obtains peak plasma levels approximately 8-12 hours afteradministration.

[0013] It is also an object of this invention to provide a controlled orsustained release pharmaceutical tablet having only a homogeneousosmotic core wherein the osmotic core component may be made usingordinary tablet compression techniques.

SUMMARY OF THE INVENTION

[0014] The foregoing objectives are met by a controlled release dosageform comprising:

[0015] (a) a core comprising:

[0016] (i) an antihyperglycemic drug;

[0017] (ii) optionally a binding agent; and

[0018] (iii) optionally an absorption enhancer;

[0019] (b) a semipermeable membrane coating surrounding the core; and

[0020] (c) at least one passageway in the semipermeable membrane.

[0021] The dosage form of the present invention can provide therapeuticlevels of the antihyperglycemic drug for twelve to twenty-four hourperiods and does not exhibit a decrease in bioavailability if taken withfood. In fact, a slight increase in the bioavailability of theantihypoglycemic drug is observed when the controlled release dosageform of the present invention is administered with food. In a preferredembodiment, the dosage form will be administered once a day, ideallywith or after a meal and most preferably with or after the evening meal,and provide therapeutic levels of the drug throughout the day with peakplasma levels being obtained between 8-12 hours after administration.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]FIG. 1 is a graph which depicts the dissolution profile insimulated intestinal fluid (pH 7.5 phosphate buffer) and simulatedgastric fluid (SGF) of the formulation described in Example 1 as testedaccording to the procedure described in United States PharmacopeiaXXIII, Apparatus 2@75 rpm.

[0023]FIG. 2 is a graph which depicts the dissolution profile insimulated intestinal fluid (pH 7.5 phosphate buffer) and simulatedgastric fluid (SGF) of the formulation described in Example 2 as testedaccording to the procedure described in United States PharmacopeiaXXIII, Apparatus 2@75 rpm.

[0024]FIG. 3 is a graph which depicts the dissolution profile insimulated intestinal fluid (pH 7.5 phosphate buffer) and simulatedgastric fluid (SGF) of the formulation described in Example 3 as testedaccording to the procedure described in United States PharmacopeiaXXIII, Apparatus 2@75 rpm.

[0025]FIG. 4 is a graph depicting the in vivo metformin plasma profileof the formulation described in Example 1 and the in vivo metforminplasma profile of the commercially available metformin HCl productGLUCOPHAGE® under fasting conditions.

[0026]FIG. 5 is a graph depicting the in vivo metformin plasma profileof the formulation described in Example 2 and the in vivo metforminplasma profile of the commercially available metformin HCl productGLUCOPHAGE® under fasting conditions.

[0027]FIG. 6 is a graph depicting the in vivo metformin plasma profileof the formulation described in Example 2 and the in vivo metforminplasma profile of the commercially available metformin HCl productGLUCOPHAGE® under fed conditions.

[0028]FIG. 7 is a graph depicting the in vivo metformin plasma profileof the formulation described in Example 3 and the in vivo metforminplasma profile of the commercially available metformin HCl productGLUCOPHAGE® under fed conditions (after breakfast).

[0029]FIG. 8 is a graph depicting the in vivo metformin plasma profileof the formulation described in Example 3 and the in vivo metforminplasma profile of the commercially available metformin HCl productGLUCOPHAGE® under fed conditions (after dinner).

DETAILED DESCRIPTION OF THE INVENTION

[0030] The term antihyperglycemic drugs as used in this specificationrefers to drugs that are useful in controlling or managingnoninsulin-dependent diabetes mellitus (NIDDM). Preferably, theantihyperglycemic drug is a biguanide such as metformin or buformin or apharmaceutically acceptable salt thereof such as metforminhydrochloride.

[0031] The binding agent may be any conventionally knownpharmaceutically acceptable binder such as polyvinyl pyrrolidone,hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose,polymethacrylate, waxes and the like. Mixtures of the aforementionedbinding agents may also be used. The preferred binding agents are watersoluble such as polyvinyl pyrrolidone having a weight average molecularweight of 25,000 to 3,000,000. The binding agent comprises approximatelyabout 0 to about 40% of the total weight of the core and preferablyabout 3% to about 15% of the total weight of the core.

[0032] The core may optionally comprise an absorption enhancer. Theabsorption enhancer can be any type of absorption enhancer commonlyknown in the art such as a fatty acid, a surfactant, a chelating agent,a bile salt or mixtures thereof. Examples of some preferred absorptionenhancers are fatty acids such as capric acid, oleic acid and theirmonoglycerides, surfactants such as sodium lauryl sulfate, sodiumtaurocholate and polysorbate 80, chelating agents such as citric acid,phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethyleneglycol-bis(β-aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA). The corecomprises approximately 0 to about 20% of the absorption enhancer basedon the total weight of the core and most preferably about 2% to about10% of the total weight of the core.

[0033] The core of the present invention which comprises theantihyperglycemic drug, the binder which preferably is apharmaceutically acceptable water soluble polymer and the absorptionenhancer is preferably formed by wet granulating the core ingredientsand compressing the granules with the addition of a lubricant into atablet on a rotary press. The core may also be formed by dry granulatingthe core ingredients and compressing the granules with the addition of alubricant into tablets or by direct compression.

[0034] Other commonly known excipients may also be included into thecore such as lubricants, pigments or dyes.

[0035] The homogeneous core is coated with a semipermeable membrane;preferably a modified polymeric membrane to form the controlled releasetablet of the invention. The semipermeable membrane is permeable to thepassage of an external fluid such as water and biological fluids and isimpermeable to the passage of the antihyperglycemic drug in the core.Materials that are useful in forming the semipermeable membrane arecellulose esters, cellulose diesters, cellulose triesters, celluloseethers, cellulose ester-ether, cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate, and cellulose acetatebutyrate. Other suitable polymers are described in U.S. Pat. Nos.3,845,770, 3;916,899, 4,008,719, 4,036,228 and 4,11210 which areincorporated herein by reference. The most preferred semipermeablemembrane material is cellulose acetate comprising an acetyl content of39.3 to 40.3%, commercially available from Eastman Fine Chemicals.

[0036] In an alternative embodiment, the semipermeable membrane can beformed from the above-described polymers and a flux enhancing agent. Theflux enhancing agent increases the volume of fluid imbibed into the coreto enable the dosage form to dispense substantially all of theantihyperglycemic drug through the passageway and/or the porousmembrane. The flux enhancing agent can be a water soluble material or anenteric material. Some examples of the preferred materials that areuseful as flux enhancers are sodium chloride, potassium chloride,sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propyleneglycol, hydroxypropyl cellulose, hydroxypropyl methycellulose,hydroxypropyl methycellulose phthalate, cellulose acetate phthalate,polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.The preferred flux enhancer is PEG 400.

[0037] The flux enhancer may also be a drug that is water soluble suchas metformin br its pharmaceutically acceptable salts or a drug that issoluble under intestinal conditions. If the flux enhancer is a drug, thepresent dosage form has the added advantage of providing an immediaterelease of the drug which is selected as the flux enhancer.

[0038] The flux enhancing agent comprises approximately 0 to about 40%of the total weight of the coating, most preferably about 2% to about20% of the total weight of the coating. The flux enhancing agentdissolves or leaches from the semipermeable membrane to form paths inthe semipermeable membrane for the fluid to enter the core and dissolvethe active ingredient.

[0039] The semipermeable membrane may also be formed with commonly knownexcipients such a plasticizer. Some commonly known plasticizers includeadipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate,triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate,citric acid esters, and those described in the Encyclopedia of PolymerScience and Technology, Vol. 10 (1969), published by John Wiley & Sons.The preferred plasticizers are triacetin, acetylated monoglyceride,grape seed oil, olive oil, sesame oil, acetyltributylcitrate,acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate,diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate,dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate,and the like. Depending on the particular plasticizer, amounts of from 0to about 25%, and preferably about 2% to about 15% of the plasticizercan be used based upon the total weight of the coating.

[0040] As used herein the term passageway includes an aperture, orifice,bore, hole, weaken area or an erodible element such as a gelatin plugthat erodes to form an osmotic passageway for the release of theantihyperglycemic drug from the dosage form. A detailed description ofthe passageway can be found in United States Patents such as U.S. Pat.Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407, 4,783,337 and5,071,607.

[0041] Generally, the membrane coating around the core will comprisefrom about 1% to about 5% and preferably about 2% to about 3% based onthe total weight of the core and coating.

[0042] In an alternative embodiment, the dosage form of the presentinvention may also comprise an effective amount of the antihyperglycemicdrug that is available for immediate release. The effective amount ofantihyperglycemic drug for immediate release may be coated onto thesemipermeable membrane of the dosage form or it may be incorporated intothe semipermeable membrane.

[0043] In a preferred embodiment the dosage form will have the followingcomposition: Preferred Most Preferred CORE: drug 50-98% 75-95% binder 0-40%  3-15% absorption enhancer  0-20%  2-10% COATING: semipermeablepolymer 50-99% 75-95% flux enhancer  0-40%  2-20% plasticizer  0-25% 2-15%

[0044] The dosage forms prepared according to the present inventionshould exhibit the following dissolution profile when tested in a USPtype 2 apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH7.5 phosphate buffer) and at 37° C.: Time (hours) Preferred MostPreferred  2  0-25%  0-15%  4 10-45% 20-40%  8 30-90% 45-90% 12 NTL 50%NTL 60% 16 NTL 60% NTL 70% 20 NTL 70% NTL 80%

[0045] NTL=NOT LESS THAN

[0046] In the preparation of the tablets of the invention, variousconventional well known solvents may be used to prepare the granules andapply the external coating to the tablets of the invention. In addition,various diluents, excipients, lubricants, dyes, pigments, dispersantsetc. which are disclosed in Remington's Pharmaceutical Sciences, 1995Edition may be used to optimize the formulations of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1

[0047] A controlled release tablet containing 850 mg of metformin HCland having the following formula is prepared as follows: I Coremetformin HCl 90.54% povidone¹, USP  4.38% sodium tribasic phosphate 4.58% magnesium stearate  0.5%

[0048] (a) Granulation

[0049] The metformin HCl is delumped by passing it through a 40 meshscreen and collecting it in a clean, polyethylene-lined container. Thepovidone, K-30, and sodium tribasic phosphate are dissolved in purifiedwater. The delumped metformin HCl is then added to a top-spray fluidizedbed granulator and granulated by spraying the binding solution ofpovidone and sodium tribasic phosphate under the following conditions:inlet air temperature of 50-70° C.; atomization air pressure of 1-3bars; and spray rate of 10-100 ml/min.

[0050] Once the binding solution is depleted, the granules are dried inthe granulator until the loss on drying is less than 2%. The driedgranules are passed through a Comil equipped with the equivalent of an18 mesh screen.

[0051] (b) Tableting

[0052] The magnesium stearate is passed through a 40 mesh stainlesssteel screen and blended with the metformin HCl granules forapproximately five (5) minutes. After blending, the granules arecompressed on a rotary press fitted with {fraction (15/32)}″ roundstandard concave punches (plain lower punch, upper punch with anapproximately 1 mm indentation pin).

[0053] (c) Seal Coating (Optional)

[0054] The core tablet is seal coated with an Opadry material or othersuitable water-soluble material by first dissolving the Opadry material,preferably Opadry Clear, in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi; and spay rate of 10-15 ml/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 2% is obtained. II Sustained Release Coating celluloseacetate (398-10)² 85% triacetin  5% PEG 400 10%

[0055] (d) Sustained Release Coating

[0056] The cellulose acetate is dissolved in acetone while stirring witha homogenizer. The polyethylene glycol 400 and triacetin are added tothe cellulose acetate solution and stirred until a clear solution isobtained. The clear coating solution is then sprayed onto the sealcoated tablets in a fluidized bed coater employing the followingconditions: product temperature of 16-22° C.; atomization pressure ofapproximately 3 bars; and spray rate of 120-150 ml/min. The sealed coretablet is coated until a theoretical coating level of approximately 3%is obtained.

[0057] The resulting tablet is tested in simulated intestinal fluid (pH7.5) and simulated gastric fluid (SGF) according to the proceduredescribed in United States Pharmacopeia XXIII, Apparatus 2@75 rpm andfound to have the following release profile: TIME (hours) % Released(SGF) % Released (pH 7.5)  2  9  12  4 27  32  8 62  82 12 82 100 16 88105 20 92 108

[0058] The release profile in pH 7.5 and SGF of the sustained releaseproduct prepared in this Example is shown in FIG. 1.

[0059]FIG. 4 depicts the in vivo metformin plasma profile of thesustained release product prepared in this Example. Also shown in FIG. 4is the in vivo metformin plasma profile of GLUCOPHAGE®, a commerciallyavailable pharmaceutical product containing the drug metformin HCl.

EXAMPLE 2

[0060] A controlled release tablet containing 850 mg of metformin HCland having the following formula is prepared as follows: I Coremetformin HCl 88.555% povidone³, USP  6.368% sodium lauryl sulfate 4.577% magnesium stearate  0.5%

[0061] (a) Granulation

[0062] The metformin HCl and sodium lauryl sulfate are delumped bypassing them through a 40 mesh screen and collecting them in a clean,polyethylene-lined container. The povidone, K-90F, is dissolved inpurified water. The delumped metformin HCl and sodium lauryl sulfate arethen added to a top-spray fluidized bed granulator and granulated byspraying with the binding solution of povidone under the followingconditions: inlet air temperature of 50-70° C.; atomization air pressureof 1-3 bars; and spray rate of 10-100 ml/min.

[0063] Once the binding solution is depleted, the granules are dried inthe granulator until the loss on drying is less than 2%. The driedgranules are passed through a Comil equipped with the equivalent of an18 mesh screen.

[0064] (b) Tableting

[0065] The magnesium stearate is passed through a 40 mesh stainlesssteel screen and blended with the metformin HCl granules forapproximately five (5) minutes. After blending, the coated granules arecompressed on a rotary press fitted with {fraction (15/32)}″ roundstandard concave punches (plain lower punch, upper punch with anapproximately 1 mm indentation pin).

[0066] (c) Seal Coating (Optional)

[0067] The core tablet is seal coated with an Opadry material or othersuitable water-soluble material by first dissolving the Opadry material,preferably Opadry Clear in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi; and spay rate of 10-15 ml/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 2% is obtained. II Sustained Release Coating celluloseacetate (398-10)⁴ 85% triacetin  5% PEG 400 10%

[0068] (d) Sustained Release Coating

[0069] The cellulose acetate is dissolved in acetone while stirring witha homogenizer. The polyethylene glycol 400 and triacetin are added tothe cellulose acetate solution and stirred until a clear solution isobtained. The clear coating solution is then sprayed onto the sealcoated tablets in a fluidized bed coater employing the followingconditions: product temperature of 16-22° C.; atomization pressure ofapproximately 3 bars; and spray rate of 120-150 ml/min. The sealed coretablet is coated until a theoretical coating level of approximately 3%is obtained.

[0070] The resulting tablet is tested in simulated intestinal fluid (pH7.5) and simulated gastric fluid (SGF) according to the proceduredescribed in United States Pharmacopeia XXIII, Apparatus 2@75 rpm andfound to have the following release profile: TIME (hours) % Released(SGF) % Released (pH 7.5)  2 13 12  4 29 27  8 55 52 12 72 71 16 81 8320 87 91

[0071] The release profile in pH 7.5 and SGF of the sustained releaseproduct prepared in this Example is shown in FIG. 2.

[0072]FIG. 5 depicts the in vivo metformin plasma profile of thesustained release product prepared in this Example under fastingconditions. FIG. 5 also shows the in vivo metformin plasma profile ofthe GLUCOPHAGE® product under fasting conditions.

[0073]FIG. 6 depicts the in vivo metformin plasma profile of thesustained release product prepared in this Example under fed conditions.FIG. 6 also shows the in vivo metformin plasma profile of theGLUCOPHAGE® product under fed conditions.

[0074]FIGS. 5 and 6 clearly show that the dosage forms prepared inaccordance with the present invention exhibit consistent bioavailabilityunder both fed and fasting conditions while the GLUOPHAGE® product'sbioavailability decreases in the presence of food.

EXAMPLE 3

[0075] A controlled release tablet containing 850 mg of metformin HCland having the same formula as in Example 2 is prepared as described inExample 2 except that an additional hole was drilled on the plain sideof the coated tablet. The additional hole had a diameter ofapproximately 1 mm.

[0076] The resulting tablet is tested in simulated intestinal fluid (pH7.5) and simulated gastric fluid (SGF) according to the proceduredescribed in United States Pharmacopeia XXIII, Apparatus 2@75 rpm andfound to have the following release profile: TIME (hours) % Released(SGF) % Released (pH 7.5)  2 13  14  4 27  28  8 50  63 12 67  84 16 84 95 20 97 102

[0077] The release profile in pH 7.5 and SGF of the sustained releaseproduct prepared in this Example is shown in FIG. 3.

[0078]FIG. 7 depicts the in vivo metformin plasma profile of thesustained release product prepared in this Example when administeredshortly after breakfast. FIG. 7 also shows the in vivo metformin plasmaprofile of the GLUCOPHAGE® product administered shortly after breakfast.

[0079]FIG. 8 depicts the in vivo metformin plasma profile of thesustained release product prepared in this Example when administeredshortly after dinner. FIG. 8 also shows the in vivo metformin plasmaprofile of the GLUCOPHAGE® product administered shortly after dinner.

[0080] Table 1 is a summary of the bioavailability comparision data,test/reference ratio, shown in FIGS. 4-8 wherein the GLUCOPHAGE® productis the reference product in a two way crossover biostudy with n=6. TABLE1 Formula FIG. Study AUC Cmax Tmax Ex. 1 4 Fasting 0.202 0.12 2.15 Ex. 25 Fasting 0.369 0.214 1.73 Ex. 2 6 Fed (bkft) 0.628 0.305 1.94 Ex. 3 7Fed (bkft) 0.797 0.528 1.82 Ex. 3 8 Fed (dinner) 0.850 0.751 2.00

[0081] The results reported in Table 1 and FIGS. 4-8 show that dosageforms prepared in accordance with the present invention exhibit anincrease in the bioavailability of the antihyperglycemic drug in thepresence of food, especially when taken with or shortly after theevening meal.

[0082] While certain preferred and alternative embodiments of theinvention have been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

We claim:
 1. A sustained release pharmaceutical formulation comprisingan antihyperglycemic drug or a pharmaceutically acceptable salt thereof,wherein said formulation provides therapeutic plasma levels of saidantihyperglycemic drug to a human patient over a 24 hour period afteradministration to said patient.
 2. The sustained release pharmaceuticalformulation of claim 1 wherein said administration is with or shortlyafter the evening meal.
 3. The sustained release pharmaceuticalformulation of claim 1 wherein the bioavailability of theantihyperglycemic drug is increased by the presence of food.
 4. Thesustained release pharmaceutical formulation of claim 1 wherein saidformulation provides a T_(max) of the antihyperglycemic drug whichoccurs at a time from about 8 hours to about 12 hours afteradministration to said human patient.
 5. The sustained releasepharmaceutical formulation of claim 1 wherein said antihyperglycemicdrug is metformin.
 6. A sustained release pharmaceutical formulationcomprising a dose of metformin or a pharmaceutically acceptable saltthereof suitable for once daily dosing, said formulation providing aT_(max) of the metformin which occurs at a time from about 8 hours toabout 12 hours after administration to a human patient.
 7. The sustainedrelease pharmaceutical formulation of claim 6 wherein saidadministration is with or shortly after the evening meal.
 8. A sustainedrelease pharmaceutical formulation comprising metformin or apharmaceutically acceptable salt thereof, said formulation suitable foronce daily dosing and providing a peak of a mean plasmaconcentration/time curve of metformin at a time from about 4 hours toabout 10 hours after administration.
 9. A sustained releasepharmaceutical formulation comprising a dose of metformin or apharmaceutically acceptable salt thereof suitable for once daily dosing,said formulation when administered with or after a meal to a humanpatient, providing a C_(max) of metformin from about 52.8% to about75.1% of the C_(max) provided by an equivalent dose of metformin in animmediate release reference formulation.
 10. The sustained releasepharmaceutical formulation of claim 9 wherein said formulation providesa T_(max) of the metformin which occurs at a time from about 8 hours toabout 12 hours after administration to said human patient.
 11. Thesustained release pharmaceutical formulation of claim 9 wherein thebioavailability of the drug is increased by the presence of food.
 12. Asustained release pharmaceutical formulation comprising a dose ofmetformin or a pharmaceutically acceptable salt thereof suitable foronce daily dosing, said formulation when administered with or after ameal to a human patient, providing a T_(max) of metformin from about182% to about 200% of the T_(max) provided by an equivalent dose ofmetformin in an immediate release reference formulation.
 13. Thesustained release pharmaceutical formulation of claim 12 wherein saidformulation provides a T_(max) of the metformin which occurs at a timefrom about 8 hours to about 12 hours after administration to said humanpatient.
 14. The sustained release pharmaceutical formulation of claim12 wherein the bioavailability of the metformin is increased by thepresence of food.
 15. A sustained release pharmaceutical formulationcomprising a dose of metformin or a pharmaceutically acceptable saltthereof suitable for once daily dosing, said formulation whenadministered in the fasted state to a human patient, providing a T_(max)of metformin from about 173% to about 215% of the T_(max) provided by anequivalent dose of metformin in an immediate release referenceformulation.
 16. The sustained release pharmaceutical formulation ofclaim 15 wherein said formulation provides a T_(max) of the metforminwhich occurs at a time from about 8 hours to about 12 hours afteradministration to a human patient.
 17. The sustained releasepharmaceutical formulation of claim 15 wherein the bioavailability ofthe metformin is increased by the presence of food.
 18. A sustainedrelease pharmaceutical formulation comprising a dose of metformin or apharmaceutically acceptable salt thereof suitable for once daily dosing,said formulation upon administration to a human patient, providing awidth at 50% of the height of a mean plasma concentration/time curvefrom about 6 hours to about 12 hours.
 19. The sustained releasepharmaceutical formulation of claim 18 wherein said formulation providesa T_(max) of the metformin which occurs at a time from about 8 hours toabout 12 hours after administration.
 20. The sustained releasepharmaceutical formulation of claim 18 wherein the bioavailability ofthe metformin is increased by the presence of food.
 21. A sustainedrelease pharmaceutical formulation comprising a dose of metformin or apharmaceutically acceptable salt thereof suitable for once daily dosing,wherein a single administration of said formulation provides a lowermean fluctuation index in the plasma than a single administration of asubstantially equal dose of an immediate release composition ofmetformin.
 22. The sustained release pharmaceutical formulation of claim21 wherein said formulation provides a T_(max) of the metformin whichoccurs at a time from about 8 hours to about 12 hours afteradministration to a human patient.
 23. The sustained releasepharmaceutical formulation of claim 21 wherein the bioavailability ofthe metformin is increased by the presence of food.
 24. A sustainedrelease pharmaceutical formulation comprising a dose of metformin or apharmaceutically acceptable salt thereof that exhibits the followingdissolution profile when tested in a USP type 2 apparatus at 75 rpm in900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at37° C.: after 2 hours 0-25% of the metformin or salt thereof isreleased; after 4 hours 10-45% of the metformin or salt thereof isreleased; after 8 hours 30-90% of the metformin or salt thereof isreleased; after 12 hours not less than 50% of the metformin or saltthereof is released; after 16 hours not less than 60% of the metforminor salt thereof is released; and after 20 hours not less than 70% of themetformin or salt thereof is released.
 25. The sustained releasepharmaceutical formulation of claim 24 wherein after administration to ahuman patient, said formulation provides a bioavailability of metforminwhich is increased by the presence of food.
 26. The sustained releasepharmaceutical formulation of claim 24 wherein after administration to ahuman patient, said formulation provides a T_(max) of metformin whichoccurs at a time from about 8 hours to about 12 hours after saidadministration.
 27. A sustained release pharmaceutical formulationcomprising a dose of metformin or a pharmaceutically acceptable saltthereof that exhibits the following dissolution profile when tested in aUSP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid(pH 7.5 phosphate buffer) and at 37° C.: after 2 hours 0-15% of themetformin or salt thereof is released; after 4 hours 20-40% of themetformin or salt thereof is released; after 8 hours 45-90% of themetformin or salt thereof is released; after 12 hours not less than 60%of the metformin or salt thereof is released; after 16 hours not lessthan 70% of the metformin or salt thereof is released; and after 20hours not less than 80% of the metformin or salt thereof is released.28. The sustained release pharmaceutical formulation of claim 27 whereinafter administration to a human patient, said formulation provides abioavailability of metformin which is increased by the presence of food.29. The sustained release pharmaceutical formulation of claim 27 whereinafter administration to a human patient, said formulation provides aT_(max) of metformin which occurs at a time from about 8 hours to about12 hours after said administration.